The Everything Therapy
The Everything Therapy
Microbiome replacement is worth a trillion dollars
The following piece was written for the 50Years progress blog to envision the impact of a potential synthetic microbiome treatment. The original version can be found here. Below is my own version, edited to remove the comparison to SaaS.
Every human has trillions of microbial cells inside of them, digesting their food, covering their skin and living in their lungs. There’s been thousands of articles over the past decade about how important the microbiome is to human health. People have been saying that treating it will change the shape of healthcare. But it hasn’t happened yet.
Today, microbiome treatments rely on fecal transplants. This is where doctors take a donor’s poop and put it into a patient, either in pill or through a tube up the colon. While fecal transplants are only FDA-approved to treat Clostridium difficile infections, doctors are investigating using them for everything from Alzheimer's to diabetes to cancer.1 But the current technique of taking poop from one person and putting it into another person is shitty because it isn’t standardized. Microbes can vary wildly donor to donor and can bring new problems along, such as multi-drug resistant pathogenic bacteria or viruses.2
To explore what might be possible, I worked with the 50Years team to explore the potential of a cocktail of microbes grown in the lab and given to patients as a first-line defense against 20 different diseases. First we dove into the research on each of these diseases, estimating a causal probability based on meta-analyses of microbes addressing disease. Then we found market sizes and patient populations for these diseases, and put all of it into a handy spreadsheet here. The result: A treatment that creates a healthy gut microbiome would be a first-line treatment for markets totaling over $500B per year and impacting more than a billion people.
That microbe cocktail will tackle an absolutely massive market for the most vulnerable people among us. And it has the potential to drop healthcare spending in the long term by addressing diseases far closer to the cause, rather than treating symptoms or by-products generated by an unhealthy microbiome.
So how would you make a microbiome replacement cocktail?
Bioengineers would need to identify and manufacture an ensemble of microbes that’s safe, consistent from patient to patient and tuned for healthy microbiome function. Despite $1.7B in research funding3 and over $2 billion4 in startup funding over the last 10 years, this doesn’t exist yet.5 When it does, it’s going to treat a billion people. Because the ensemble represents a healthy baseline, a doctor won’t even necessarily need a full diagnosis. If a problem is vaguely related to inflammation, metabolism or neurology? Just give them a few pills full of microbes and see if it helps.6
Let’s dive into the details and justifications for all the diseases that microbe ensembles would be able to treat.
Just like with C. diff, replacing your gut biome helps treat other infectious diseases, in the gut or not. This includes cholera, salmonella, recurrent UTIs and multidrug resistant infections.7 Microbial ensembles also prevent various bacteria from causing gastric cancer, and generally block colon cancer progression.8
The gut is also the largest immune organ in the body, and effective communication between the immune system and the gut is critical for health.9 Raising mice without a microbiome cripples their immune system,10 and dysbiosis (an unhealthy microbiome) is just as bad.11 If your cells in your gut attack you, that can lead to an autoimmune disorder which can be treated by a fecal transplant.12 This insight reaches multiple indications, including arthritis,13 chronic fatigue,14 allergies,15 baldness,16 and aging17 on top of the obvious ones like colitis and Crohn's.18
In addition to directly treating these diseases, chemotherapies (a $10B market) and immunotherapies (an $110B market) can both be modified by the gut microbiome, and microbial ensembles can turn non-responders into responders.19 This would give a microbial ensemble a multiplicative effect on existing therapeutics.
Your microbiome processes all of the food that you eat, and how it does that is critical to regulating hunger and nutrient absorption. If your microbiome keeps you hungry, you’re going to gain weight.20 On top of that, a microbial ensemble can change how your body processes sugars, helping deal with diabetes and other metabolic disorders,21 as well as reducing the risk of the biggest killer in the world - heart disease.22
In neurological health, the root cause of multiple sclerosis is potentially Clostridium perfringens,23 and fecal transplants have treated MS effectively in small studies.24 There hasn’t been as much study for Parkinson’s25 and Alzheimer’s,26 but there’s good evidence that an unhealthy microbiome can contribute to both. It’s possible microbial ensembles will slow or even stop these neurodegenerative disorders.27 It likely won’t reverse damage already done, but even slowing these diseases would impact tens of millions of people globally.
The immune system forms early on in life, so microbial ensembles for children would have benefits for many of the indications listed here. In addition, setting the microbiome early could prevent autoimmune disorders that cause everything from diabetes to acne. Persephone Biosciences is doing just this by sequencing the gut microbiomes of healthy infants to discover a set of microbes that could foster a healthy microbiome. While industrialization, changing diets, and antibiotics are all partially to blame for microbial changes, C-sections and lack of breast-feeding also both play a role. Persephone will initially treat babies born via C-section (27 million28 each year!), and then expand to treat all children, reversing thousands of years of microbial evolution, and preventing many of the diseases mentioned. This will be a market worth at least tens of billions of dollars annually as the science matures, given 130 million children are born each year.
Unfortunately, making an effective standardized fecal transplant is hard. Several microbiome companies have failed, including Seres, Evelo, and Finch,29 highlighting the challenges in making a good microbiome therapy. This is a new clinical space without significant precedent, and there are numerous question marks from strain selection to manufacturing and delivery.
But for every company that’s failed, two have sprung up in their place.30 Some have even raised hundreds of millions: Seres Therapeutics has raised $537M, and Vedanta Biosciences has raised $433M. Both academic and industrial research into the microbiome is accelerating. This is spurred on by hurricane-strength tech tailwinds. Sequencing costs have dropped 1,000,000,000x in the last 25 years alongside other -omics. At the same time, AI model parameter counts have improved at least 10,000,000x. The microbiome is a high-dimensional stew of microbes, nutrients and proteins, and we need every tool we can get to understand it well enough to rebuild it from the ground up.
While it’s been common to investigate microbiomes via in-vivo testing, in-vitro testing is rapidly gaining popularity. Gut-on-chip technology is in the lead, able to capture important interactions in vitro.31 While currently rare, this market is expected to 5x in the next 5 years.32 Other high-throughput microfluidic approaches are also contributing, allowing combinatorial testing of strain combinations and conditions to test thousands of interactions at once.33
The development of metagenomics gave us a way to see what microbes are present in the microbiome, but it’s not enough information. Metabolomics is the next tool, as it reveals the metabolism and chemistry in our internal bioreactors. That’s led to significant advances like understanding the role of butyrate, but there are far more metabolites to map.34 There’s also been some incredible advances in metaproteomics,35 as well as direct genetic manipulation of the microbiome that provide pieces of the puzzle.36
All of these new techniques generate an enormous amount of high-dimensional data, which is hard to process and harder to generate appropriate models from. But artificial intelligence is well-suited to help us build effective synthetic microbial communities that can replace unbalanced microbiomes.37 And AI technology is getting vastly cheaper.
The first company to properly take advantage of these technologies and make an effective and scalable synthetic fecal transplant will have a massive first-mover advantage. Doctors will try it to treat everything named above - and more. Positive results will get that same microbial ensemble approved for more indications beyond the first, and negative results will provide valuable data to improve the treatment. There will likely also be challenges in manufacturing initially, and so the first mover will have massive demand that facilitates scale-up financing. These factors mean that followers will have to spend far more capital per indication, both for running studies and for manufacturing microbial ensembles. Being the first mover could be exceptionally profitable.
Current Trends and Challenges of Fecal Microbiota Transplantation-An Easy Method That Works for All? The challenge: “This procedure implies a careful donor choice, fine collection and handling of fecal material, and a balanced preparation of the recipient and consequent administration of the prepared content.”
No one has documented COVID transmission via a fecal transplant, but oh boy are they worried about it. Notably: “Therefore, several FMT centers and stool banks have suspended the active performance of FMT and the recruitment of FMT donors” Fecal Microbiota Transplantation: Is It Safe? - PMC
Microbiome startups from the last 10 years.
There is no synthetic fecal transplant, and we don’t know how to make one yet, but people are working on the problem. Synthetic microbial communities (SynComs) of the human gut: design, assembly, and applications | FEMS Microbiology Reviews | Oxford Academic Even attempts to propagate a good ‘wild type’ fecal transplant haven’t worked out Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial - PMC
“The final aim is to stimulate discussion and open new therapeutic perspectives among experts in the use of fecal microbiota transplantation not only in Clostridioides difficile infection but as one of the first strategies to be used to ameliorate a number of human conditions.” Fecal Microbiota Transplantation as New Therapeutic Avenue for Human Diseases
Additionally, the current FDA-approved fecal transplant treatment is four pills taken once a day. So it wouldn’t even be a difficult thing to prescribe. https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides
Also some viruses and blood-based infections as well, via leaky guts. Full article: The potential utility of fecal (or intestinal) microbiota transplantation in controlling infectious diseases A fecal transplant would probably need less personalization than a phage therapy against antibiotic resistant bugs
Fecal transplants prevent colorectal cancer progression Fecal microbiota transplantation inhibits colorectal cancer progression: Reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses
The first line of the abstract Mammalian Gut Immunity - PMC
This is an older study, but this is the summary from the above paper. Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats
FMT in the treatment of autoimmune diseases is effective and relatively safe, from the last line of the abstract. Safety and efficacy of fecal microbiota transplantation for autoimmune diseases and autoinflammatory diseases: A systematic review and meta-analysis
There’s good reason to believe that fecal transplants would help treat arthritis. The role of microbiome in rheumatoid arthritis treatment but clinical trials have been inconclusive for psoriatic arthritis Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial though there is a case study showing that a fecal transplant effectively treated rheumatoid arthritis Fecal microbiota transplantation for rheumatoid arthritis: A case report - PMC
An older study showed a very basic fecal transplant had 58% response rates for chronic fatigue, though later studies have been a bit more mixed. https://journals.lww.com/ajg/fulltext/2012/10001/bacteriotherapy_in_chronic_fatigue_syndrome__cfs__.1481.aspx The underlying theory: Multi-‘omics of gut microbiome-host interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients - PMC
Allergies are modulated by microbiome Microbiome and Allergic Diseases and allergies can be treated by microbiome treatments The gut microbiome-immune axis as a target for nutrition-mediated modulation of food allergy - ScienceDirect
Alopecia areata is caused by an immune reaction, and can likely be treated & prevented with fecal transplants. The Gut and Skin Microbiome in Alopecia: Associations and Interventions - PMC
Both colitis and Crohn's are known as ‘inflammatory bowel diseases’ where inflammation of the gut snowballs. Fecal transplantation for treatment of inflammatory bowel disease - PMC
Fecal transplants improve chemotherapy and immunotherapy responses Immunotherapy in Colorectal Cancer: Potential of Fecal Transplant and Microbiota-Augmented Clinical Trials Fecal Microbiota Transplantation Prevents Intestinal Injury, Upregulation of Toll-Like Receptors, and 5-Fluorouracil/Oxaliplatin-Induced Toxicity in Colorectal Cancer
Obesity is a big problem, and it’s inarguable that it’s both caused by and treatable with the microbiome. The Influence of the Gut Microbiome on Obesity in Adults and the Role of Probiotics, Prebiotics, and Synbiotics for Weight Loss Do Antibiotics Cause Obesity Through Long-term Alterations in the Gut Microbiome? A Review of Current Evidence
Metabolic fecal transplants for metabolic syndrome, type 1 & 2 diabetes. Fecal microbiota transplantation in the metabolic diseases: Current status and perspectives - PMC
This is both direct Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease | Nature and indirect, in that fatty liver disease is known to cause cardiovascular problems Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials, and your gut biome is often responsible for causing and maintaining a fatty liver Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity | Nature
Multiple sclerosis can be treated by fecal transplants The Potential Role of Fecal Microbiota Transplant in the Reversal or Stabilization of Multiple Sclerosis Symptoms: A Literature Review on Efficacy and Safety: because the ultimate cause of multiple sclerosis is likely microbiome-derived epsilon toxin from Clostridium perfringens Clostridium epsilon toxin is excessive in multiple sclerosis and provokes multifocal lesions in mouse models - PMC Oral Multiple Sclerosis Drugs Inhibit the In vitro Growth of Epsilon Toxin Producing Gut Bacterium, Clostridium perfringens Prevention and treatment of Clostridium perfringens epsilon toxin intoxication in mice with a neutralizing monoclonal antibody (c4D7) produced in Nicotiana benthamiana
Parkinson’s may result from a highly oxidizing gut microbiome. Association of Gut Microbiome Dysbiosis with Neurodegeneration: Can Gut Microbe-Modifying Diet Prevent or Alleviate the Symptoms of Neurodegenerative Diseases? - PMC
Alzheimer’s isn’t as definite as MS, but there are some strong arguments. Emerging role of gut microbiota dysbiosis in neuroinflammation and neurodegeneration
“The evidence discussed in this review does suggest that gut microbiome modification through FMT may be a novel treatment for AD, PD, MS and ALS that should be investigated in more depth. At the very least, it appears to provide some relief from symptoms with minimal (if any) adverse side effects; this is incredibly valuable in an area where treatments are either missing or limited in their long-term efficacy” The Role of Fecal Microbiota Transplantation in the Treatment of Neurodegenerative Diseases: A Review
21% of children born via C-section Global increased cesarean section rates and public health implications: A call to action - PMC, and 130M babies born globally.
Seres, Evelo, and Finch have all failed clinical trials:
https://www.clinicaltrialsarena.com/news/seres-drug-fails-trial/?cf-view
https://medcitynews.com/2023/11/microbiome-evelo-biosciences-flagship-pioneering-inflammation/
US examples include Vedanta, Rebiotix, Seres, Evelo and Siolta. European examples include MaaT Pharma, EnteroBiotix. Australia has Microba and Servatus.
This work is impressive, but very hard to duplicate because of the technical complexity. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip | Nature Biomedical Engineering
Here’s a review Emerging microfluidic technologies for microbiome research - PMC One clear example is Microbial interaction network inference in microfluidic droplets - PMC which is the kind of technology behind Concerto Biosciences’ data generation platform.
Metabolomics usually involves small-molecule mass-spec. A metabolomics pipeline for mechanistic interrogation of the gut microbiome - PMC Butyrate is one of the big wins of metabolomics, Role of Butyrate, a Gut Microbiota Derived Metabolite, in Cardiovascular Diseases: A comprehensive narrative review Butyrate’s role in human health and the current progress towards its clinical application to treat gastrointestinal disease - ScienceDirect
There’s been clever approaches involving conjugative plasmids with transposons, Metagenomic engineering of the mammalian gut microbiome in situ | Nature Methods CRISPR systems Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome and bacteriophage CRISPR-based engineering of phages for in situ bacterial base editing | PNAS.
Unsurprisingly, this is the basis of multiple companies. Rebiotix, Concerto and Siolta are all taking this approach. More are quietly embracing this approach, not mentioning AI but still posting job openings for AI data scientists https://microbe.med.umich.edu/opportunities/staff/scientist-modeling-statistics-vedanta-biosciences Here’s an academic review of what this kind of thing looks like Harnessing machine learning for development of microbiome therapeutics - PMC